methyl 2-chlorobenzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (+)-trans-1-[2-Hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)- -4,6-dimethoxyphenyl]-1-ethanone (compound 13), was prepared from (+)-trans-[1-Methyl-3-(2,4,6-trimethoxy-phenyly-pyrrolidin-2-yl]-methanol using the procedures described in examples 6 & 7. Compound 13, (0.7 g, 2.2 mmol) was reacted with methyl 2-chlorobenzoate (1.15 g, 6.75 mmol) in dry DMF (15 mL) in the presence of NaH (50%, 0.54 g, 11.25 mmol), using the procedure described in example 8 to afford the title compound(4). to afford the title compound(4)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound(5) was converted into (−)-trans-1-[2-Hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4,6-dimethoxyphenyl]-1-ethanone(compound(10) using the procedures described in examples 6 & 7. Compound(10) (0.75 g, 2.4 mmol), was reacted with methyl 2-chlorobenzoate (1.36 g, 7.9 mmol) in dry DMF (15 mL) in the presence of NaH (50%, 0.582 g, 12.9 mmol), using the procedure described in example 8 to get the title compound(11). to get the title compound(11)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound(5) was converted into (−)-trans-1-[2-Hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4,6-dimethoxyphenyl]-1-ethanone(compound(10) using the procedures described in examples 6 & 7. Compound(10) (0.75 g, 2.4 mmol), was reacted with methyl 2-chlorobenzoate (1.36 g, 7.9 mmol) in dry DMF (15 mL) in the presence of NaH (50%, 0.582 g, 12.9 mmol), using the procedure described in example 8 to get the title compound(11). to get the title compound(11)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyl lithium in hexane (1.58N, 55.6 ml, 88 mmol) was added dropwise to a solution of dimethyl methylphosphonate (10.9 g, 88 mmol) in 100 ml of anhydrous THF with stirring at -78° C. under argon atmosphere. After 30 minutes, a solution of methyl o-chlorobenzoate (6.0 g, 35.2 mmol) in 10 ml of anhydrous THF was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was allowed to warm to 0° C., diluted with 5.3 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-o-chlorophenyl-2-oxoethylphosphonate (8.2 g, 31.2 mmol, yield 88.7%, b.p. 142°-145° C./0.09 mmHg), which was assigned the structure by the following data: the mixture was stirred for 30 minutes to warm to 0° C. concentrated 30 ml of water was added to the residue the mixture was extracted with ethyl acetate (50 ml×2) The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1) dried over anhydrous sodium sulfate concentrated The residue was distilled under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of n-butyl lithium in hexane (1.58N, 55.6 ml, 88 mmol) was added dropwise to a solution of dimethyl methylphosphonate (10.9 g, 88 mmol) in 100 ml of anhydrous THF with stirring at -78° C. under argon atmosphere. After 30 minutes, a solution of methyl o-chlorobenzoate (6.0 g, 35.2 mmol) in 10 ml of anhydrous THF was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was allowed to warm to 0° C., diluted with 5.3 ml of acetic acid and 10 ml of water, and concentrated. 30 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-o-chlorophenyl-2-oxoethylphosphonate (8.2 g, 31.2 mmol, yield 88.7%, b.p. 142°-145° C./0.09 mmHg), which was assigned the structure by the following data: the mixture was stirred for 30 minutes to warm to 0° C. concentrated 30 ml of water was added to the residue the mixture was extracted with ethyl acetate (50 ml×2) The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1) dried over anhydrous sodium sulfate concentrated The residue was distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of o-chlorobenzoic acid (7.6 g, 48.6 mmol) in 50 ml of ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl o-chlorobenzoate (6.0 g, 35.2 mmol, yield 72.4%, b.p. 92°-93° C./7 mmHg), which was assigned the structure by the following data: cooled After concentration the residue was distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 230 ml of a 2M solution of NaHMDS in THF are introduced under nitrogen in a 250 ml of THF. The solution is cooled to −60° C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at −60° C., 29.8 g of methyl 2-chlorobenzoate are added and the mixture is stirred at −60° C. for 45 min and then allowed to return to 0° C. The reaction medium is poured on to 500 ml of ice-cold 2N HCl, extraction is carried out with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying and concentrating to dryness, purification is carried out by chromatography on silica (gradient: heptane up to heptane/AcOEt 80/20). 7.3 g of the expected compound are obtained. to return to 0° C the extract is washed with water After drying concentrating to dryness, purification

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-(2-Chlorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid is prepared, according to the procedure used in stages 1A)-1E), from (4-methoxyphenyl)acetic acid and methyl 2-chlorobenzoate. In the final stage of this procedure, 5 g of methyl 542-chlorophenyl)-4-(4-methoxyphenyl)-2-thiophenecarboxylate and 1.11 g of sodium hydroxide pellets are added to 30 ml of methanol and 3 ml of dioxane. The reaction medium is heated at 50-60° C. for 5 hours. It is evaporated to dryness, water is added and the impurities are extracted with ether. The aqueous phase is acidified and the expected compound is extracted with ether. After drying and evaporating, 3.5 g of the expected compound are obtained. 5-(2-Chlorophenyl)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid is prepared It is evaporated to dryness, water is added the impurities are extracted with ether the expected compound is extracted with ether After drying evaporating